The LIM domain-only genes LMO1 and LMO2 are translocated in acute T cell leukemia (T-ALL) and have been shown to be oncogenes in T lymphoid cells. LMO4, the fourth member of this family, is overexpressed in more than 50% of sporadic breast cancers, suggesting a role in breast oncogenesis. We recently found that LMO4 interacts with the breast/ ovarian tumor suppressor BRCA1 and that LMO4 can repress its transcriptional activity. Since proto-oncogene deregulation can result from activating mutations in their coding or regulatory sequences, we explored whether the LMO4 gene undergoes somatic mutagenesis in breast cancer. Mutation analysis of the coding and 3' untranslated regions of the LMO4 gene was performed on 82 primary breast and 22 tumor cell lines. A somatic mutation was detected in one primary breast cancer, at the 3' end of exon 2, but was not present in normal DNA derived from the same patient. This mutation causes a frame-shift and potentially results in a truncated LMO4 polypeptide, LIMImut, lacking the second LIM domain. This mutant protein could still bind Ldb I but no longer associated with CtIP or BRCA1. Our results show that somatic mutations within the LMO4 gene do occur in breast cancer but at a very low frequency. Thus, the primary mechanism by which LMO4 is deregulated in breast cancers appears to reflect overexpression of the gene rather than the acquisition of activating genetic mutations. (C) 2003 Wilev-Liss, Inc.